Abstract Alzheimer?s disease (AD) is a major cause of dementia, affecting millions of elderly patients in our aging society, and thus represents a severe health care challenge. Currently available drugs may provide some temporary relief but none of them is able to halt disease progression or cure. To develop better therapies a clear understanding of the disease etiology is urgently needed. Recent data suggest the rate of synaptic activity and particularly rate of vesicle endocytosis is critically important for the processing of amyloid precursor protein (APP) into beta-amyloid (Abeta), a source of major toxic component in AD. The exact molecular mechanism connecting synaptic transmission to APP processing is still unknown. My laboratory?s long-term goal is to identify new, molecular therapeutic target(s) in the brain that can help to prevent synaptic dysfunction and neurodegeneration to preserve cognition and memory. The objective in this application is to examine a specific class of proteins ? the vesicular membrane associated proteins (VAMPs/synaptobrevins) and their role in synaptic release and Abeta production. Our strong preliminary results establish synaptobrevin1/VAMP1 (syb1), a member of the SNARE (SNAP Receptor) complex, as a novel object for this innovative research of dementia: a) in human genetic screens single nucleotide polymorphism (SNP) variants of the VAMP1 gene encoding syb1 are significantly associated with late onset AD; b) SNPs associated with increased expression of VAMP1 increase the risk of AD and SNPs associated with lower VAMP1 expression reduces the risk of AD; c) in the new VAMP1 KO mice endogenous Abeta40 and Abeta42 levels are substantially reduced. Based on these observations, the central hypothesis is that VAMP1 is a key coupling protein between vesicular release and APP processing. We hypothesize that variations in VAMP1 level alter the coupling of synaptic transmission to APP processing and therefore have profound effect on Abeta production. The rationale for the proposed research is that understanding the molecular mechanism that activates Abeta production will provide a novel, better way to lower Abeta levels and it may prevent or delay cognitive decline in AD patients. We will test this hypothesis by pursuing three specific aims: 1) Examine the effect of synaptobrevin expression level on synaptic activity and Abeta production in neurons using the novel VAMP1 KO mice. 2) Identify the structural elements of VAMP1 coupling synaptic activity to amyloidogenic pathway of APP processing. 3) Evaluate the effects of reduced VAMP1 levels on preventing cognitive impairment in the AD model Tg2576 mice in vivo. These aims will be tested through extensive analysis of synaptic activity, endocytosis and Abeta production with sophisticated methods including multi-electrode and patch-clamp electrophysiology and live fluorescence microscopy. The proposed research is significant because it has the potential to identify VAMP1 as the first synaptic regulator of amyloidogenesis and novel target for AD diagnosis and therapy.